PK of Special Populations

## Why Special Populations Matter

Standard pharmacokinetic parameters are derived from studies in healthy adults aged 18-65. Special populations — neonates, elderly, obese, pregnant, and critically ill patients — deviate significantly from these norms due to physiological differences that alter every ADME process.

## Neonates and Infants

Neonates have profoundly different PK profiles compared to adults:

- **Absorption**: Higher gastric pH (achlorhydria at birth), slower gastric emptying, immature gut transporters
- **Distribution**: Higher total body water (70-80% vs 55-60%), lower fat content, lower plasma protein concentrations, higher free drug fractions
- **Metabolism**: Immature Phase I (CYP) and Phase II (UGT) enzymes. CYP3A7 predominates at birth; CYP3A4 matures over months. Glucuronidation is deficient — chloramphenicol causes "gray baby syndrome" due to inability to conjugate the drug.
- **Excretion**: GFR at birth is ~2-4 mL/min (vs 120 mL/min in adults). Reaches adult values by age 6-12 months. Drugs like aminoglycosides require extended dosing intervals.

## Elderly Patients (>65 years)

Aging progressively alters pharmacokinetics:

- **Decreased hepatic blood flow** (40% reduction by age 65) reduces first-pass metabolism, increasing oral bioavailability of high-extraction drugs
- **Reduced hepatic mass and CYP activity** slows Phase I metabolism; Phase II is relatively preserved
- **Declining GFR** (~1 mL/min/year after age 40) necessitates dose reduction for renally cleared drugs
- **Increased body fat, decreased lean mass and total body water** increases Vd for lipophilic drugs and decreases it for hydrophilic drugs
- **Decreased albumin** increases free fraction of highly bound drugs

## Obese Patients

Obesity alters drug distribution more than other PK processes:

- **Lipophilic drugs** (diazepam, voriconazole) have increased Vd — may need higher loading doses but standard weight-based maintenance
- **Hydrophilic drugs** (aminoglycosides, vancomycin) distribute primarily in lean mass — dosing on total body weight causes overdosing
- **Adjusted body weight** formulas are used for many drugs: ABW = IBW + 0.4 x (TBW - IBW)
- **Hepatic metabolism** may be enhanced (increased liver blood flow) or impaired (NAFLD) depending on the drug

## Critically Ill Patients

Critical illness creates a "pharmacokinetic storm" with multiple simultaneous alterations:

- **Augmented renal clearance** (ARC) in sepsis/trauma: GFR > 130 mL/min leads to subtherapeutic levels of beta-lactams and vancomycin
- **Third-spacing**: capillary leak increases Vd for hydrophilic drugs
- **Hypoalbuminemia**: increases free drug fraction
- **Organ hypoperfusion**: reduces hepatic and renal clearance
- **Extracorporeal circuits**: ECMO and CRRT add additional drug clearance and sequestration

## Key Takeaways

- Neonatal PK differs in every ADME parameter due to organ immaturity
- Elderly patients need renal dose adjustments and careful metabolic drug selection
- Obesity primarily affects distribution — use appropriate weight scalars
- Critical illness alters PK unpredictably, favoring therapeutic drug monitoring
- One size does not fit all — individualized dosing is essential in special populations